Dataset Information

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection.

ABSTRACT:

Background

Viral infection activates innate immune pathways and interferons (IFNs) play a pivotal role in the outcome of a viral infection. Ubiquitin modifications of host and viral proteins significantly influence the progress of virus infection. Ubiquitin-conjugating enzyme E2s (UBE2) have the capacity to determine ubiquitin chain topology and emerge as key mediators of chain assembly.

Methods

In this study, we screened the functions of 34 E2 genes using an RNAi library during Dengue virus (DENV) infection. RNAi and gene overexpression approaches were used to study the gene function in viral infection and interferon signaling.

Results

We found that silencing UBE2J1 significantly impaired DENV infection, while overexpression of UBE2J1 enhanced DENV infection. Further studies suggested that type I IFN expression was significantly increased in UBE2J1 silenced cells and decreased in UBE2J1 overexpressed cells. Reporter assay suggested that overexpression of UBE2J1 dramatically suppressed RIG-I directed IFN? promoter activation. Finally, we have confirmed that UBE2J1 can facilitate the ubiquitination and degradation of transcription factor IFN regulatory factor 3 (IRF3).

Conclusion

These results suggest that UBE2 family member UBE2J1 can negatively regulate type I IFN expression, thereby promote RNA virus infection.

SUBMITTER: Feng T

PROVIDER: S-EPMC6114777 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection.

Feng Tingting T Deng Lei L Lu Xiaochuan X Pan Wen W Wu Qihan Q Dai Jianfeng J

Virology journal 20180829 1

<h4>Background</h4>Viral infection activates innate immune pathways and interferons (IFNs) play a pivotal role in the outcome of a viral infection. Ubiquitin modifications of host and viral proteins significantly influence the progress of virus infection. Ubiquitin-conjugating enzyme E2s (UBE2) have the capacity to determine ubiquitin chain topology and emerge as key mediators of chain assembly.<h4>Methods</h4>In this study, we screened the functions of 34 E2 genes using an RNAi library during D ...[more]

PMID: 30157886

Similar Datasets

Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.

Dataset Information

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection.

Background

Methods

Results

Conclusion

Publications

Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets